INTRODUCTION & OBJECTIVES: It is currently recommended to perform open radical nephroureterectomy (oRNU) with bladder cuff excision in patients with locally advanced (cT3-4 or cN1-2) upper tract urothelial carcinoma (laUTUC). We tested the hypothesis that bladder recurrence-free survival (BRFS), metastasis-free survival (MFS), cancer-specific survival (CSS) and overall survival (OS) are not influenced by the surgical approach in patients with laUTUC using a large multicenter series. MATERIAL & METHODS: This was a multicenter retrospective cohort study including 361 patients with preoperative cT3-4 cM0 or cN1-2 cM0 laUTUC treated with open or minimally invasive RNU from 1999 to 2019 at 21 academic centers in Europe, Asia, and the United States. Missing values of relevant baseline characteristics were estimated through multiple imputation of chained equations. Baseline patients' heterogeneity was balanced using a 1:1 propensity score matching estimated using logistic regression. Uni- and multivariable Cox regression analyses for bladder recurrence, metastasis, cancer-specific death and overall death were performed according to clinical and pathological characteristics. Kaplan Meier (KM) estimates and log-rank test were used to compare BRFS, MFS, CSS and OS according to clinical and pathological features. RESULTS: Median follow-up was 28 months. After propensity score matching, two cohorts of 115 laUTUC patients each with similar baseline and preoperative tumor characteristics were obtained. In the matched cohort, pT ≥ 3 stage was found in 84 (73%) and 67 (58.3%) patients in the oRNU and miRNU groups, respectively. Positive lymph nodes were detected in 27 (23.5%) and 32 (27.8%) patients in the oRNU and miRNU groups, respectively. In the multivariable regression analysis, pT ≥ 3 and positive lymph nodes were associated with an increased risk of metastasis (HR 3.22, 95% CI 1.26-8.23, and HR 4.03, 95% CI 2.05-7.89, respectively). The surgical approach (oRNU vs. mi RNU) did not influence oncological outcomes as shown by uni- and multivariable analyses as well as Kaplan-Meier estimates, regardless of pT stage. CONCLUSIONS: The oncological outcomes of laUTUC for cT3-4 cM0 or cN1-2 cM0 disease are comparable whether RNU is performed via an open or minimally invasive approach. Therefore, the decision to opt for oRNU or miRNU should be guided by the surgeon's expertise and the patient's comorbidities, rather than concerns over long-term oncological outcomes associated with either surgical technique.

• Klíčová slova
• Locally advanced Utuc, Minimally-invasive nephroureterectomy, Open nephroureterectomy, Upper tract urothelial cancer, Utuc,
• MeSH
• karcinom z přechodných buněk * chirurgie   patologie   mortalita   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• miniinvazivní chirurgické výkony metody   MeSH
• míra přežití MeSH
• nádory ledvin * chirurgie   patologie   mortalita   MeSH
• nádory močovodu * chirurgie   patologie   mortalita   MeSH
• nefroureterektomie * metody   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• staging nádorů MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• srovnávací studie MeSH

BACKGROUND AND OBJECTIVE: The role of genetic variants in response to systemic therapy in muscle-invasive bladder cancer (MIBC) is still elusive. We assessed variations in genes involved in DNA damage repair (DDR) before and after cisplatin-based neoadjuvant chemotherapy (NAC) and correlation of alteration patterns with DNA damage and response to therapy. METHODS: Matched tissue from 46 patients with MIBC was investigated via Ion Torrent-based next-generation sequencing using a self-designed panel of 30 DDR genes. Phosphorylation of γ-histone 2A.X (H2AX) was analyzed via immunohistochemistry to evaluate DNA damage. Genetic variants were analyzed along with clinical data and quantitative phospho-H2AX data using the Kaplan-Meier method, Cox regression analysis, and factor analysis of mixed data. KEY FINDINGS AND LIMITATIONS: Twenty-five patients (54%) had a response (

• Klíčová slova
• Cisplatin-based neoadjuvant chemotherapy, DNA repair genes, Muscle-invasive bladder cancer, Mutation, Next-generation sequencing,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Immune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are likely affected by immortal time bias and do not represent causal effects. The aim of this study was to assess the effect of irAEs on outcomes while correcting for immortal time bias, using target trial emulation (TTE). METHODS: TTE was contrasted to adjusted naïve and time-updated Cox models. We performed a multi-institutional retrospective study involving mUC patients under ICI. The primary objective was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the influence of irAEs on objective response rates (ORRs) to ICI and the influence of systemic corticosteroids on outcomes. RESULTS: Among 335 patients (median age: 69 yrs), 69.6% received ICI in the second line or further lines. During a median follow-up of 21.1 months, 122 (36.4%) patients developed irAEs of any grade (grade ≥ 3: 14.9%). Hazard ratios (HRs) for PFS ranged from 0.37 for naïve adjusted Cox model to 0.88 (95% confidence interval (CI), 0.59-1.30) with time-updated covariates, and from 0.41 to 1.10 (95% CI, 0.69-1.75) for OS. TTE accounting for immortal time bias yielded a HR of 1.02 (95% CI, 0.72-1.44) for PFS, and 0.90 (95% CI, 0.62-1.30) for OS. In contrast to the naïve Cox model (HR = 2.26, 95% CI 1.26-4.05), the presence of irAEs was no longer a predictive factor for improved ORR in time-updated Cox models (HR = 1.27, 95% CI 0.68-2.36) and TTE (HR = 1.43, 95% CI 0.89-2.29). In patients with irAEs, systemic corticosteroids did not negatively impact survival. CONCLUSION: Using TTE, we were able to show that the occurrence of irAEs is no longer associated with better survival or improved response rates to ICI in mUC patients, in contrast to the naïve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures.

• Klíčová slova
• Adverse events, Immortal time bias, Immune checkpoint inhibitors, Immunotherapy, Metastatic, Target trial emulation, Urothelial cancer,
• MeSH
• inhibitory kontrolních bodů * škodlivé účinky   terapeutické užití   MeSH
• karcinom z přechodných buněk farmakoterapie   mortalita   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory močového měchýře farmakoterapie   mortalita   imunologie   patologie   MeSH
• nežádoucí účinky léčiv etiologie   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• urologické nádory farmakoterapie   mortalita   imunologie   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• inhibitory kontrolních bodů * MeSH

PURPOSE: Chemotherapy can potentially enhance the activity of immune checkpoint inhibitors by promoting immune priming. The phase Ib/II JAVELIN Chemotherapy Medley trial (NCT03317496) evaluated first-line avelumab + concurrent chemotherapy in patients with advanced urothelial carcinoma or non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Avelumab 800 or 1,200 mg was administered continuously every 3 weeks with standard doses of cisplatin + gemcitabine in patients with urothelial carcinoma, or carboplatin + pemetrexed in patients with nonsquamous NSCLC. Dual primary endpoints were dose-limiting toxicity (DLT; phase Ib) and confirmed objective response (phase Ib/II). RESULTS: In phase Ib, urothelial carcinoma and NSCLC cohorts received avelumab 800 mg (n = 13 and n = 6, respectively) or 1,200 mg (n = 6 each) + chemotherapy. In evaluable patients with urothelial carcinoma treated with avelumab 800 or 1,200 mg + chemotherapy, DLT occurred in 1/12 (8.3%) and 1/6 (16.7%), respectively; no DLT occurred in the NSCLC cohort. In phase II, 35 additional patients with urothelial carcinoma received avelumab 1,200 mg + chemotherapy. Across all treated patients, safety profiles were similar irrespective of avelumab dose. Objective response rates (95% confidence internal) with avelumab 800 or 1,200 mg + chemotherapy, respectively, across phase Ib/II, were 53.8% (25.1-80.8) and 39.0% (24.2-55.5) in urothelial carcinoma, and 50.0% (11.8-88.2) and 33.3% (4.3-77.7) in NSCLC. CONCLUSIONS: Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of similar combination regimens. Conclusions about clinical activity are limited by small patient numbers. SIGNIFICANCE: This phase Ib/II trial evaluated avelumab (immune checkpoint inhibitor) administered concurrently with standard first-line chemotherapy in patients with advanced urothelial carcinoma or advanced nonsquamous NSCLC without actionable mutations. Efficacy and safety appeared consistent with previous studies of similar combinations, although patient numbers were small.

• MeSH
• cisplatina aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• deoxycytidin analogy a deriváty   aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• dospělí MeSH
• gemcitabin MeSH
• humanizované monoklonální protilátky * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• karboplatina aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• karcinom z přechodných buněk farmakoterapie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory plic * farmakoterapie   patologie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   patologie   MeSH
• pemetrexed terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• urologické nádory farmakoterapie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• avelumab MeSH Prohlížeč
• cisplatina MeSH
• deoxycytidin MeSH
• gemcitabin MeSH
• humanizované monoklonální protilátky * MeSH
• karboplatina MeSH
• pemetrexed MeSH

Despite the rapid progress in the field of personalized medicine and the efforts to apply specific treatment strategies to patients based on the presence of pathogenic variants in one, two, or three genes, patient response to the treatment in terms of positive benefit and overall survival remains heterogeneous. However, advances in sequencing and bioinformatics technologies have facilitated the simultaneous examination of somatic variants in tens to thousands of genes in tumor tissue, enabling the determination of personalized management based on the patient's comprehensive genomic profile (CGP). CGP has the potential to enhance clinical decision-making and personalize innovative treatments for individual patients, by providing oncologists with a more comprehensive molecular characterization of tumors. This study aimed to highlight the utility of CGP in routine clinical practice. Here we present three patient cases with various advanced cancer indicated for CGP analysis using a combination of SOPHiA Solid Tumor Solution (STS, 42 genes) for DNA and SOPHiA RNAtarget Oncology Solution (ROS, 45 genes and 17 gene fusions with any random partners) for RNA. We were able to identify actionable genomic alterations in all three cases, thereby presenting valuable information for future management of these patients. This approach has the potential to transform clinical practice and greatly improve patient outcomes in the field of oncology.

• MeSH
• genomika MeSH
• individualizovaná medicína MeSH
• lidé MeSH
• nádory * diagnóza   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Kidney and bladder cancers share etiology and relatively good recent survival, but long-term studies are rare. We analyzed survival for these cancers in Denmark, Finland, Norway (NO), and Sweden (SE) over a 50-year period (1971-2020). Relative 1- and 5-year survival data were obtained from the NORDCAN database, and we additionally calculated conditional 5/1-year survival. In 2016-2020, 5-year survivals for male kidney (79.0%) and bladder (81.6%) cancers were best in SE. For female kidney cancer, NO survival reached 80.0%, and for bladder cancer, SE survival reached 76.1%. The magnitude of 5-year survival improvements during the 50-year period in kidney cancer was over 40% units; for bladder cancer, the improvement was over 20% units. Survival in bladder cancer was worse for women than for men, particularly in year 1. In both cancers, deaths in the first year were approximately as many as in the subsequent 4 years. We could document an impressive development for kidney cancer with tripled male and doubled female 5-year survival in 50 years. Additionally, for bladder cancer, a steady improvement was recorded. The current challenges are to curb early mortality and target treatment to reduce long-term mortality.

• Klíčová slova
• conditional survival, relative survival, surgery, treatment, uro-oncology,
• Publikační typ
• časopisecké články MeSH